Antidiabetic preparation for oral administration

ABSTRACT

There is provided a single preparation which directly decreases both of the post prandial blood glucose level and the fasting blood glucose level close to normal levels, by release-sustaining a drug capable of decreasing the post prandial blood glucose level of diabetic patients close to the normal level, or mixing a controlled release drug capable of decreasing the post prandial blood glucose level close to the normal level with an immediate release drug. It is particularly preferable that the drug capable of decreasing the post prandial blood glucose level close to the normal level is nateglinide, repaglinide, or mitiglinide (KAD-1229).

BACKGROUND OF THE INVENTION

[0001] The present invention relates to an antidiabetic, particularly toa preparation for directly controlling, namely decreasing both a postprandial blood glucose level and a fasting blood glucose level ofdiabetic patients with one preparation to make these levels close tonormal levels.

[0002] Ordinary antidiabetics are antidiabetics for decreasing either apost prandial blood glucose level or a fasting blood glucose level tomake it close to a normal level. As antidiabetics for decreasing a postprandial blood glucose level to make it close to a normal level,nateglinide has been developed, and it is described in, for example,Japanese Patent Publication No. 15,221/1992 or Japanese Patent Laid-OpenNo. 194,969/1998. Further, antidiabetics for decreasing a fasting bloodglucose level to make it close to a normal level are described in, forexample, Kondo Nobuo, Nippon Rinsho, vol. 55, 1997, extra ed., p. 159and the like. In recent years, for treating diabetes, it has beenconsidered important that both a post prandial blood glucose level and afasting blood glucose level are decreased to make them close to normallevels.

[0003] However, there have been no preparations for decreasing bothlevels to make them close to normal levels.

DISCLOSURE OF THE INVENTION

[0004] The invention is to provide a preparation for directly decreasingboth a post prandial blood glucose level and a fasting blood glucoselevel by one preparation to make them close to normal levels.

[0005] The present inventors have assiduously conducted investigationsto solve the foregoing problems, and have consequently found that both apost prandial blood glucose level and a fasting blood glucose level canbe decreased by one preparation to make them close to normal levels.This finding has led to the completion of the invention.

[0006] That is, the invention provides an antidiabetic preparation fororal administration characterized by containing active ingredient (s)for decreasing blood glucose level of diabetic patients and having aform to make both a post prandial blood glucose level and a fastingblood glucose level of diabetic patients close to normal levels.

[0007] The invention further provides an antidiabetic preparation fororal administration characterized by containing nateglinide in which ina dissolution test for 1 hour, a dissolution rate of the activeingredient is at least 1% and less than 70% at pH of 1.2, 4.0 and 6.8.

[0008] The invention still further provides an antidiabetic preparationfor oral administration containing nateglinide in which a dissolutionrate of nateglinide is dependent on pH and in a dissolution test for 1hour, a dissolution rate of nateglinide at pH of 1.2 is at least 20%lower than a dissolution rate thereof at pH of 6.8.

[0009] The invention furthermore provides an antidiabetic preparationfor oral administration containing nateglinide in which in a dissolutiontest for 1 hour, a dissolution rate of the active ingredient at pH of4.0 is less than 20% and a dissolution rate of the active ingredient atpH of 6.0 is at least 20%.

[0010] The invention moreover provides an antidiabetic preparation fororal administration containing nateglinide and at least one materialselected from the group consisting of polysaccharide derivatives,polyacrylic acid derivatives, polylactic acid derivatives,polyoxyethylene derivatives, polyvinyl pyrrolidone derivatives,polyvinyl alcohol derivatives, oils and surfactants, nateglinide beingdispersed in the material or being emulsified or microencapsulated withthe material.

[0011] The invention moreover provides an antidiabetic preparation fororal administration containing nateglinide and at least one materialselected from the group consisting of polysaccharide derivatives (exceptfor hydroxypropylmethyl cellulose), polyacrylic acid derivatives,polylactic acid derivatives, polyvinyl pyrrolidone derivatives,polyvinyl alcohol derivatives, oils and surfactants, nateglinide beingcoated with the material.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 is a graph showing a dissolution profile (n=3) of immediaterelease granules in a JP 2 solution by a puddle method (test solution900 ml: 50 rpm) in Example 1.

[0013]FIG. 2 is a graph showing a dissolution profile (n=3) of hardenedoil (hydrogenated castor oil) matrix granules in a JP 2 solution by apuddle method (test solution 900 ml: 50 rpm) in Example 2.

[0014]FIG. 3 is a graph showing a dissolution profile (n=3) of ethylcellulose matrix granules in a JP 2 solution by a puddle method (testsolution 900 ml: 50 rpm) in Example 3.

[0015]FIG. 4 is a graph showing a dissolution profile (n=3) of themixture of immediate release granules and hardened oil matrix granulesin a JP 2 solution by a puddle method (test solution 900 ml: 50 rpm)when mixing immediate release granules with hardened oil matrix granules(2:8 nateglinide weight ratio) in Example 4.

[0016]FIG. 5 is a graph showing a release amount of nateglinide (n=3) ofthe mixture of immediate release granules and hardened oil matrixgranules in a JP 2 solution by a puddle method (test solution 900 ml: 50rpm) when mixing immediate release granules with hardened oil matrixgranules (2:8 nateglinide weight ratio) in Example 4.

[0017]FIG. 6 is a graph showing a dissolution pH profile (n=3) ofenteric coated granules A, B and C in a neutral pH region by a puddlemethod (test solution 900 ml: 50 rpm) in Example 8.

[0018]FIG. 7 is a graph showing a pH dependence (n=3) of a dissolutionrate for 60 minutes by a puddle method (test solution 900 ml: 50 rpm)when mixing immediate release granules with enteric coated granules A(5:5 nateglinide weight ratio) in Example 9.

[0019]FIG. 8 is a graph showing a change in blood glucose level whenadministering enteric coated granules A, B and C to Beagle dogs justbefore feeding (nateglinide 9 mg/kg) (control: n=6, enteric coatedgranules: n=3) in Example 14.

[0020]FIG. 9 is a graph showing a change in blood glucose level whenadministering a nateglinide preparation to Beagle dogs just beforefeeding (control, immediate release tablets: n=6, immediate releaseportion+enteric coated granules A, enteric coated granules A: n=3) inExample 15.

[0021]FIG. 10 is a graph showing a change in concentration ofnateglinide in plasma when administering a nateglinide preparation toBeagle dogs just before feeding (average±SE (standard error), n=6,provided n=3 at concentrations in 3, 8, 9, 12 and 24 hours on anateglinide preparation of immediate release portion (nateglinide: 60mg)+enteric coated granules A (nateglinide: 90 mg)) in Example 19.

[0022]FIG. 11 is a graph showing a change in blood glucose level whenadministering a nateglinide preparation to Beagle dogs just beforefeeding (average, change in blood glucose level when a blood glucoselevel just before feeding is rated as 100%, n=6, provided n=3 at levelsin 3, 8, 9, 12 and 24 hours on a nateglinide preparation of immediaterelease portion (nateglinide: 60 mg)+enteric coated granules A(nateglinide: 90 mg) in Example 19.

[0023]FIG. 12 is a graph showing a dissolution profile (n=3) of erosionmatrix tablets and coated erosion matrix coating tablets in a JP 2solution by a puddle method (test solution 900 ml: 50 rpm) in Example20.

[0024]FIG. 13 is a graph showing a dissolution profile (n=3) of drycoated tablets in a JP 2 solution by a puddle method (test solution 900ml: 50 rpm) in Example 22.

[0025]FIG. 14 is a graph showing a change in concentration ofnateglinide in plasma when administering dry coated tablets to Beagledogs just before feeding (average±SE, n=3, provided n=6 on an immediaterelease preparation (nateglinide: 60 mg)) in Example 22.

[0026]FIG. 15 is a graph showing a change in blood glucose level whenadministering dry coated tablets to Beagle dogs just before feeding(average, change in blood glucose level when a blood glucose level justbefore administration is rated as 100%, n=3, provided n=6 on a controland an immediate release preparation (nateglinide: 60 mg)) in Example22.

BEST MODE FOR CARRYING OUT THE INVENTION

[0027] In the invention, “to make both a post prandial blood glucoselevel and a fasting glucose level of diabetic patients close to normallevels” means that a post prandial blood glucose level and a fastingglucose level of diabetic patients are decreased to make them close to apost prandial blood glucose level and a fasting glucose level of healthypersons respectively.

[0028] Active ingredient(s) for decreasing a blood glucose level ofdiabetic patients may include first active ingredient(s) for decreasinga post prandial blood glucose level and second active ingredient (s) fordecreasing a fasting glucose level.

[0029] In this case, the first active ingredient(s) for decreasing apost prandial blood glucose level is/are drug(s) for making a postprandial blood glucose level of diabetic patients to a blood glucoselevel of healthy persons. It includes drug(s), for example, afast-acting post prandial blood glucose regulator such as nateglinide orthe like, and an α-glycosidase inhibitor such as acarbose or the like.Especially, nateglinide is preferable.

[0030] Nateglinide is a fast-acting antidiabetic agent which functionsto stimulate insulin production. Thus, the fast-acting post prandialblood glucose regulator may be any other agent which stimulates insulinproduction. Examples of such agents include repaglinide (PRANDIN) andanalogs thereof and mitiglinide (KAD-1229) and analogs thereof. Thus,throughout this disclosure these agents may be used in place ofnateglinide.

[0031] Further, the second active ingredient (s) for decreasing afasting blood glucose level is/are drug(s) for making a fasting glucoselevel of diabetic patients to a fasting glucose level of healthypersons. It includes drug(s), for example, a sulfonylurea drug (SU drug)such as tolbutamide or the like, a biguanide drug such as metforminhydrochloride or the like, and an insulin sensitizer such astroglitazone or the like.

[0032] The invention includes a case where the preparation has both animmediate release form and a controlled release form of the activeingredient(s) or a single form of sustained release belonged tocontrolled release.

[0033] In this case, the active ingredient(s) for decreasing a bloodglucose level may be the first active ingredient(s) used singly or thefirst active ingredient(s) and the second active ingredient(s) used incombination. In these cases, each of the first active ingredient(s) andthe second active ingredient(s) may be single or plural.

[0034] In the invention, the single use of the first activeingredient(s) is preferable, the combined use of nateglinide and anotheractive ingredient(s) or the single use of nateglinide are morepreferable. The single use of nateglinide is especially preferable.

[0035] The “immediate release form of the active ingredient (s)” herereferred to is an immediate release tablet described in Japanese PatentLaid-Open No. 194,969/1998 or various dosage forms showing its similarrelease behavior. Those which quickly elute a drug in the stomach afteradministration are included therein. Meanwhile, the “controlled releaseform of the active ingredient(s)” includes (i) a single form thatcontinuously releases a drug, namely, a single form of sustainedrelease, and (ii) a single form that releases a drug after the lapse ofa fixed period of time.

[0036] Examples thereof include a pH dependent type, a time dependenttype, a time limit release type, a gastrointestinal site specificrelease type and the like. Of these, a pH dependent type, a timedependent type and a time limit release type are preferable.

[0037] In the invention, it is especially preferable to contain a singleactive ingredient for decreasing a blood glucose level and have a formto continuously release the active ingredient from post prandial throughfasting in oral administration.

[0038] As the single active ingredient for decreasing the blood glucoselevel here, nateglinide is preferably used.

[0039] Here, the form to continuously release the active ingredient inthe invention includes a combination of an immediate release form and acontrolled release form which continuously releases the activeingredient and a single form of sustained release in controlled releaseof the active ingredient.

[0040] The immediate release form and the controlled release form or thesustained release form of the active ingredient (s) for decreasing theblood glucose level can easily be obtained by dispersing the activeingredient(s) for decreasing the blood glucose level in a matrixmaterial, coating the same with a coating material, emulsifying the samewith an emulsion material or microencapsulating the same with amicrocapsule material. Such a method is known as a matrix method, atablet coating method, a granule coating method, an emulsionmethod-microencapsulation method or the like. Further, other methods arealso available.

[0041] It is advisable that the matrix material, the coating material,the emulsion material and the microcapsule material are independentlyselected from the group consisting of polysaccharide derivatives,polyacrylic acid derivatives, polylactic acid derivatives,polyoxyethylene derivatives, polyvinyl pyrrolidone derivatives,polyvinyl alcohol derivatives, oils and surfactants.

[0042] The matrix method here is a method in which a drug is dispersedin the matrix material to control a release behavior. Examples of thematrix material include the foregoing polysaccharide derivatives, oilsand polyacrylic acid derivatives, and the like. Any pharmaceuticallyacceptable compounds that form such a porous structure as to be able todiffuse a drug, water or the like in water will do.

[0043] Preferable examples thereof include cellulose derivatives, anethyl acrylate•methyl methacrylate•chlorotrimethylammoniumethylmethacrylate copolymer, a methacrylic acid•methyl methacrylatecopolymer, a methacrylic acid•ethyl acrylate copolymer, polylactic acid,a polylactic acid copolymer, polyoxyethylene, polyvinyl pyrrolidone, a1-vinyl-2-pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol,glyceride, a polyoxyethylene nonionic surfactant and a phospholipid, andthese are used either singly or in admixture of two or more.

[0044] Preferable examples of cellulose derivatives here include ethylcellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl celluloseacetate succinate, sodium carmelose, carboxymethylethyl cellulose,cellulose acetate phthalate and hydroxyethyl cellulose, and these areused either singly or in admixture of two or more.

[0045] Further, methyl cellulose and mixtures with the foregoingcompounds are also preferable.

[0046] Examples of a method of making a matrix include a high-speedagitation granulation method, a fluidized bed granulation method, a meltgranulation method, a solvent removal method, a slug tableting methodand the like. A method in which a drug and a matrix material can bemixed can be employed as a method of producing a matrix in theinvention.

[0047] As types of a matrix, a non-erosion (non-collapsible) matrix inwhich a matrix structure does not collapse during release of a drug, andan erosion (collapsible) matrix in which a matrix structure collapseswith release of a drug. In case of using a water-insoluble material, anon-erosion matrix is obtained. In case of using a water-solublematerial, an erosion matrix is obtained.

[0048] At this time, various release behaviors can be obtained uponchanging the type of the matrix material, the ratio of the matrixmaterial and the drug or the production method. The drug releasebehavior is preferably a pH dependent type, a time dependent type or atime limit release type. However, the invention can be completed withother release behaviors so long as a drug can be released to make a postprandial blood glucose level and a fasting blood glucose level close tonormal levels by decreasing these blood glucose levels. The specificweight ratio of the matrix material and the drug is 1:99 to 99:1,preferably 10:90 to 90:10.

[0049] The coating method includes a granule coating method and a tabletcoating method. The granule coating method is a method in which coregranules containing a drug are subjected to coating to control therelease behavior.

[0050] As the coating material used in the coating method in theinvention, for example, the foregoing polyacrylic acid derivatives,polysaccharide derivatives and oils are mentioned. Pharmaceuticallyacceptable compounds that form such a porous structure as to be able todiffuse a drug, water or the like in water or pharmaceuticallyacceptable compounds of which the solubility is dependent on pH areavailable. Preferable examples thereof include cellulose derivatives, anethyl acrylate•methyl methacrylate•chlorotrimethylammonium-ethylmethacrylate copolymer, a methacrylic acid•methyl methacrylatecopolymer, a methacrylic acid•ethyl acrylate copolymer, polylactic acid,a polylactic acid copolymer, polyoxyethylene, polyvinyl pyrrolidone, a1-vinyl-2-pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol,glyceride, a polyoxyethylene nonionic surfactant and a phospholipid, andthese are used either singly or in admixture of two or more. Ascellulose derivatives here, the same examples as listed on the matrixmaterial are preferable.

[0051] Examples of the granule coating method include a fluidized bedcoating method, a tumbling bed coating method and the like. Any methodin which a coating film can be formed on core granules can be employedas the coating method in the invention.

[0052] The core granules here refer to original granules which aresubjected to the coating. The core granules can be produced by a methodof obtaining granules containing a drug and having a form appropriatefor the coating, for example, an extrusion granulation method, ahigh-speed agitation granulation method, a spray drying method or thelike.

[0053] The tablet coating method is a method in which core tabletscontaining a drug are coated. As the tablet coating method, a wetcoating method or the like is mentioned. A method in which a coatingfilm can be formed on core tablets can be employed as the coating methodin the invention. The core tablets here refer to original tablets whichare subjected to the coating. The core tablets can be produced by amethod of obtaining tablets containing a drug and having a formappropriate for the coating, for example, a wet agglomerated granulescompression method, a direct tableting method or the like.

[0054] Various release behaviors such as pH dependent release, timedependent release and the like can be obtained by changing a coatingmaterial, a coating film composition, a coating film thickness, acomposition of core granules or tablets, a method of producing coregranules or tablets, a coating method and the like.

[0055] The drug release behavior is preferably a pH dependent type, atime dependent type or a time limit release type. However, the inventioncan be completed with other release behaviors so long as a drug can bereleased to make a post prandial blood glucose level and a fasting bloodglucose level close to normal levels by decreasing these blood glucoselevels. Incidentally, examples of the pH dependent release includeenteric coated granules and the like.

[0056] The emulsion method or the microencapsulation method is a methodin which a drug is incorporated into an emulsion or a microcapsule tocontrol the release behavior.

[0057] Examples of the material of the emulsion or the microcapsuleinclude polysaccharide derivatives, polyacrylic acid derivatives, oils,surfactants and the like. Any pharmaceutically acceptable compounds thatform such a structure as to control permeation of a drug from inside theemulsion or the microcapsule to the outside thereof in water will do.

[0058] Preferably, one or a admixture of two or more selected from thegroup consisting of cellulose derivatives, an ethyl acrylate•methylmethacrylate•chlorotrimethylammoniumethyl methacrylate copolymer, amethacrylic acid-methyl methacrylate copolymer, a methacrylic acid•ethylacrylate copolymer, polylactic acid, a polylactic acid copolymer,polyoxyethylene, polyvinyl pyrrolidone, a 1-vinyl-2-pyrrolidone•vinylacetate copolymer, polyvinyl alcohol, glyceride, a polyoxyethylenenonionic surfactant and a phospholipid can be used as inactiveingredient (s) material of the emulsion or the microcapsule in theinvention. Preferable examples of cellulose derivatives here includeethyl cellulose, hydroxypropylmethyl cellulose phthalate,hydroxypropylmethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose acetate succinate, sodium carmelose,carboxymethylethyl cellulose, cellulose acetate phthalate andhydroxyethyl cellulose, and these are used either singly or in admixtureof two or more. Further, methyl cellulose and mixtures with theforegoing compounds are also preferable.

[0059] Examples of the emulsion method or the microencapsulation methodinclude a submerged drying method, a phase separation method using anaqueous solution, an organic solvent or the like, a hotmelt dispersionmethod, a spray drying method, an aerial suspension coating method, afluidized bed coating method, a tumbling bed coating method, aninterfacial polymerization method, a submerged cure-coating method andthe like.

[0060] With respect to the drug release behavior, various releasepatterns such as pH dependent release, time dependent release and thelike can be obtained by changing an inactive ingredient, a composition,a particle diameter, a production method or the like.

[0061] A pH dependent type, a time dependent type, a time limit releasetype are preferable. However, other release behaviors are also availableso long as a drug can be released to make both a post prandial bloodglucose level and a fasting blood glucose level close to normal levelsby decreasing these blood glucose levels.

[0062] The second embodiment of the invention is an antidiabeticpreparation for oral administration characterized in that in adissolution test for 1 hour with one preparation containing nateglinide,the dissolution rate of the active ingredient is at least 1% and lessthan 70% at pH of 1.2, 4.0 and 6.8 (this embodiment corresponds to atime dependent release type of a matrix or the like, and to Examples 2,3, 20 and 22). With respect to the dissolution test method here, in adissolution test method by a puddle method (test solution 900 ml: 50rpm) of Japanese Pharmacopeia 13 (hereinafter referred to as “JP”), JPdisintegration test method 1st solution (JP 1 solution) containing 0.6w/v % polysorbate 80, a McIIvaine buffer solution of pH=4.0 diluted to ¼and containing 0.5 w/v % polysorbate 80 and a JP disintegration testmethod 2nd solution (JP 2 solution) are used as a test solution. It isadvisable that the second embodiment is conducted with a matrix, acoating, an emulsion or a microcapsule.

[0063] The third embodiment of the invention is an antidiabetic for oraladministration characterized in that in one preparation containingnateglinide, a dissolution rate of nateglinide is dependent on pH and ina dissolution test for 1 hour, a dissolution rate of nateglinide at pHof 1.2 is at least 20% lower than a dissolution rate thereof at pH of6.8. (This embodiment corresponds to a pH dependent release type, a timedependent release type and the like, and to Example 9). With respect tothe dissolution test method here, in a dissolution test method by a JPpuddle method (test solution 900 ml: 50 rpm), a JP disintegration testmethod 1st solution (pH 1.2) containing 0.6 w/v % polysorbate 80 and aJP disintegration test method 2nd solution (pH 6.8) are likewise used asa test solution. It is advisable that the third embodiment is conductedwith a matrix, a coating, an emulsion or a microcapsule.

[0064] The fourth embodiment of the invention is an antidiabetic fororal administration characterized in that in a dissolution test for 1hour with one preparation containing nateglinide, a dissolution rate ofthe active ingredient at pH of 4.0 is less than 20% and a dissolutionrate of the active ingredient at pH of 6.0 is at least 20% (thisembodiment corresponds to a pH dependent release type, and to entericcoated granules C in Example 8).

[0065] With respect to the dissolution test method here, in adissolution test method by a JP puddle method (test solution 900 ml: 50rpm), a McIIvaine buffer solution of pH=4.0 diluted to ¼ and containing0.5 w/v % polysorbate 80 and a Clark-Lubs buffer solution (potassiumdihydrogenphosphate-sodium hydroxide type: pH 6.0 or 6.5) are used as atest solution.

[0066] In the invention, it is further advisable that the dissolutionrate of the active ingredient at pH of 6.5 is at least 60%.

[0067] The preparation having the foregoing dissolution characteristicscan be obtained, as stated above, by dispersing the active ingredientfor decreasing the blood glucose level in the matrix material, coatingthe same with the coating material, emulsifying the same with theemulsion material or microencapsulating the same with the microcapsulematerial.

[0068] The fifth embodiment of the invention is an antidiabeticpreparation for oral administration containing nateglinide and at leastone material selected from the group consisting of polysaccharidederivatives, polyacrylic acid derivatives, polylactic acid derivatives,polyoxyethylene derivatives, polyvinyl pyrrolidone derivatives,polyvinyl alcohol derivatives, oils and surfactants, nateglinide beingdispersed in the material or being emulsified or microencapsulated withthe material.

[0069] Further, the sixth embodiment of the invention is an antidiabeticpreparation for oral administration containing nateglinide and at leastone material selected from the group consisting of polysaccharidederivatives (except for hydroxypropylmethyl cellulose), polyacrylic acidderivatives, polylactic acid derivatives, polyvinyl pyrrolidonederivatives, polyvinyl alcohol derivatives, oils and surfactants,nateglinide being coated with the material.

[0070] In the fifth embodiment, the material is preferably selected fromethyl cellulose, hydroxypropylmethyl cellulose phthalate,hydroxypropylmethyl cellulose acetate succinate, sodium carmelose,carboxymethylethyl cellulose, cellulose acetate phthalate, hydroxyethylcellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, anethyl acrylate•methyl methacrylate•chlorotrimethyl-ammoniumethylmethacrylate copolymer, a methacrylic acid•methyl methacrylatecopolymer, a methacrylic acid•ethyl acrylate copolymer, polylactic acid,a polylactic acid copolymer, polyoxyethylene, polyvinyl pyrrolidone, a1-vinyl-2-pyrrolidone•vinyl acetate copolymer, polyvinyl alcohol,glyceride, a polyoxyethylene nonionic surfactant and a phospholipid,these being used either singly or in admixture of two or more.

[0071] Moreover, methyl cellulose and mixtures with the foregoingcompounds are also preferable.

[0072] Further, in the sixth embodiment, it is preferably selected fromthe group consisting of ethyl cellulose, hydroxypropylmethyl cellulosephthalate, hydroxypropylmethyl cellulose acetate succinate, sodiumcarmelose, carboxymethylethyl cellulose, cellulose acetate phthalate,hydroxyethyl cellulose, hydroxypropyl cellulose, an ethylacrylate•methyl methacrylate•chlorotrimethylammoniumethyl methacrylatecopolymer, a methacrylic acid•methyl methacrylate copolymer, amethacrylic acid•ethyl acrylate copolymer, polylactic acid, a polylacticacid copolymer, polyvinyl pyrrolidone, a 1-vinyl-2-pyrrolidone•vinylacetate copolymer, polyvinyl alcohol, glyceride, a polyoxyethylenenonionic surfactant and a phospholipid, these being used either singlyor in admixture of two or more. Moreover, methyl cellulose and mixtureswith the foregoing compounds are also preferable.

[0073] As the material in the fifth and sixth embodiments,hydroxypropylmethyl cellulose phthalate or a methacrylic acid•ethylacrylate copolymer is further preferable. The methacrylic acid•ethylacrylate copolymer here is preferably a methacrylic acid copolymer LD ora dry methacrylic acid copolymer LD. With these, nateglinide can beformed into a controlled release preparation.

[0074] The preparation for oral administration in the invention includesvarious forms such as granules, tablets, powders, capsules and the like.

[0075] A form of sustained release of an active ingredient fordecreasing a blood glucose level alone can make both a post prandialblood glucose level and a fasting blood glucose level close to normallevels. For example, it is possible in a form satisfying the fourthembodiment.

[0076] Specifically, hydroxypropylmethyl cellulose phthalate,hydroxypropylmethyl cellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and a methacrylic acid copolymerL can be used as the material of such a preparation. The use ofhydroxypropylmethyl cellulose phthalate is especially preferable.

[0077] The combined use of an immediate release form and a controlledrelease form can decrease both a post prandial blood glucose level and afasting blood glucose level with good accuracy to make them close tonormal levels. A mixing ratio of a controlled release form of a drug fordecreasing a post prandial blood glucose level to a normal level and animmediate release form of a drug for decreasing a post prandial bloodglucose level to a normal level is 1:99 to 99:1, preferably 10:90 to90:10 in terms of a weight ratio of a drug for decreasing a postprandial blood glucose level to make the same close to a normal level. Amixing method and a mixed form are not limited in the invention. Asustained release form can be used singly. The mixed form includesgranules capsules, tablets, solutions and the like.

[0078] For example, when immediate release granules are mixed withcontrolled release granules, the form is granules. When these granulesare encapsulated, the form is capsules. Tablets are obtained bytableting these mixed granules, tableting the respective granules individed layers (multilayer tablet), or using a controlled release tabletformed of controlled release granules as an inner shell and immediaterelease granules as an outer shell and tableting them (dry coatedtablet).

[0079] Further, in case of using the preparation of the invention, itcan be administered at a dose of 1 mg to 10 g per day as an activeingredient, though depending on the ratio of the form for decreasing apost prandial blood glucose level to make it close to a normal level andthe form for decreasing a fasting blood glucose level to make it closeto a normal level and the extent of the pharmaceutical effect of theactive ingredient (s).

EXAMPLES

[0080] The invention is illustrated specifically below by referring toExamples. However, these are preferable embodiments of the invention,and the invention is not limited thereto.

[0081] Designing of an Immediate Release Portion

Example 1 Immediate Release Granules

[0082] Nateglinide (375.0 g), 637.5 g of lactose monohydrate and 450.0 gof hydroxypropyl cellulose having a low degree of substitution weremixed with a high-speed agitation granulator for 10 minutes.Subsequently, 1,035 g of a binding solution of 15 g of hydroxypropylcellulose in water was added, and granulation was conducted for 2.5minutes. The total amount of the resulting granular product wasuniformly granulated with a new speed mill, and dried with a fluidizedbed drier. The obtained granules were screened through a sieve of 850μm. The granular product remaining on the sieve of 850 μm was forciblypassed through the sieve, and both products were mixed to form immediaterelease granules.

[0083] The dissolution profile in the second solution of the JapanesePharmacopeia disintegration test method was evaluated by a JP puddlemethod (test solution 900 ml: 50 rpm). Consequently, it was identifiedthat almost 100% nateglinide was released in 20 minutes (FIG. 1).

[0084] Designing of a Controlled Release Portion with Matrix Granules

Example 2 Matrix Granules Using Hardened Oil (Controlled Release)

[0085] Hardened oil (1.5 g) was melted in a mortar by heating, 39 ofnateglinide was added thereto, and these were thoroughly kneaded. Afterthe temperature was returned to room temperature, the kneaded productwas granulated, and was screened to obtain matrix granules of 180 to 710μm.

[0086] The dissolution of the resulting matrix granules in the JP 2solution was evaluated by the JP 13 puddle method (test solution 900 ml:50 rpm). The formation of the matrix made the dissolution rate ofnateglinide slower than that of immediate release granules (FIG. 2). Thecontrolled release considered mainly effective for decreasing a fastingblood glucose level to make it close to a normal level was enabled.

Example 3 Matrix Granules Using Ethyl Cellulose (Controlled Release)

[0087] Ethyl cellulose (1.5 g) and 3.0 g of nateglinide were dissolvedin ethanol, and ethanol was distilled off using an evaporator. Theresulting solid matter was further vacuum-dried at 60° C. for 3 hours ormore. The thus-obtained solid matter was granulated, was screened toobtain matrix granules of 180 to 710 μm.

[0088] The dissolution of the resulting matrix granules in the JP 2solution was evaluated by the JP 13 puddle method (test solution 900 ml:50 rpm). The formation of the matrix made the dissolution rate ofnateglinide slower than that of immediate release granules (FIG. 3). Thecontrolled release considered mainly effective for decreasing a fastingblood glucose level to make it close to a normal level was enabled.

Example 4 Dissolution Profile when Mixing Immediate Release Granuleswith Controlled Release Hardened Oil Matrix Granules

[0089] The dissolution profile in the JP2 solution when mixing theimmediate release granules described in Example 1 with the controlledrelease hardened oil matrix granules described in Example 2 (2:8nateglinide weight ratio) was evaluated by the JP 13 puddle method (testsolution 900 ml: 50 rpm).

[0090] The drug was released at a rate of 65% within 60 minutes, andthen gradually released over a period of 6 hours (FIG. 4).

[0091] The release control presumed to be effective for decreasing apost prandial blood glucose level and a fasting blood glucose level tomake them close to normal levels was enabled (FIG. 5).

[0092] Designing of a release control portion with coating granules

Example 5 Core Granules 1 for Coating

[0093] Nateglinide (250 g), 425 g of lactose monohydrate and 10 g ofhydroxypropyl cellulose were suspended and dissolved in 815 g of waterusing a homogenizer. The suspension was then added to 300.0 g ofhydroxypropyl cellulose having a low degree of substitution, and thesewere kneaded. The mixture was extrusion-granulated using an extrusiongranulator. The resulting granular product was uniformly granulated witha marumerizer (Fuji Paudal, Q-230 model) to be spherical. Subsequently,the product was dried with a fluidized bed drier. Fractions of 850 μm to1,400 μm were obtained by screening, and designated core granules 1 forcoating.

Example 6 Core Granules 2 for Coating

[0094] Nateglinide (250 g), 425 g of lactose monohydrate and 300.0 g ofhydroxypropyl cellulose having a low degree of substitution were mixedwith a high-speed agitation granulator for 10 minutes. Subsequently, 690g of a binding solution of 10 g of hydroxypropyl cellulose in water wasadded, and granulation was conducted for 5 minutes. Then, the productwas dried with a fluidized bed drier. Fractions of 850 μm to 1,400 μmwere obtained by screening, and designated core granules 2 for coating.

Example 7 Core Granules 3 for Coating

[0095] Nateglinide (250 g) and 725 g of lactose monohydrate were mixedwith a high-speed agitation granulator for 10 minutes. Subsequently, 690g of a binding solution of 10 g of hydroxypropyl cellulose in water wasadded, and granulation was conducted for 5 minutes. Then, the productwas dried with a fluidized bed drier. Fractions of 850 μm to 1,400 μmwere obtained by screening, and designated core granules 3 for coating.

[0096] Designing of a pH Dependent Release Control Portion

Example 8 Enteric Coated Granules (Controlled Release)

[0097] The coating core granules 1 described in Example 5 were subjectedto enteric coating by a fluidized bed coating method. A recipe of acoating solution is shown in Tables 1 and 2 (dry methacrylic acidcopolymer LD, methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate 220824). A dry methacrylic acid copolymer LD (tradename: Eudragit L100-55, Röhm), a methacrylic acid copolymer S (tradename: Eudragit S100, Röhm) and hydroxypropylmethyl cellulose phthalate220824 (trade name: HP-50, Shin-etsu Kagaku) were used as an entericmaterial.

[0098] On enteric coated granules (enteric coated granules A, B and Crespectively) obtained by coating the core granules with 33 w/w % of thedry methacrylic acid copolymer LD, 34 w/w % of the methacrylic acidcopolymer S and 24 w/w % of hydroxypropylmethyl cellulose phthalate220824, the dissolution profile in the neutral pH region (puddle method(test solution 900 ml: 50 rpm), dissolution rate for 60 minutes,Clark-Lubs buffer solution) was evaluated. It was identified that theenteric coated granules A, B and C started the dissolution at pH of 6.5,7.2 and 5.5 (FIG. 6) respectively. TABLE 1 enteric material a or b  7.0%Macrogol 6000  0.7% talc  3.5% ethanol 70.0% water 18.8%

[0099] TABLE 2 hydroxypropylmethyl cellulose phthalate 220824 7.0%Macrogol 6000 0.7% talc 1.0% ethanol 73.0%  water 18.3% 

Example 9 Dissolution Profile when Mixing an Immediate Release Portion(Immediate Release Granules) with a Controlled Release Portion (EntericCoated Granules)

[0100] A dissolution rate for 60 minutes (JP 13, puddle method (testsolution 900 ml: 50 rpm), acidic pH: JP disintegration test method 1stsolution (JP 1 solution) containing 0.6 w/v % polysorbate 80, neutralpH: Clark-Lubs buffer solution) when mixing the immediate releaseportion (immediate release granules) described in Example 1 with thecontrolled release portion (enteric coated granules A (obtained bycoating the core granules with 33 w/w % of the dry metallic acidcopolymer LD) (5:5 nateglinide weight ratio)) described in Example 8 wasevaluated.

[0101] Nateglinide was dissolved from the immediate release granulesalone in the range of pH=1.2 to 6.0, and nateglinide was dissolved fromboth the immediate release granules and the enteric coated granules atpH=6.5 or more (FIG. 7). The release control presumed to be effectivefor decreasing a post prandial blood glucose level and a fasting bloodglucose level to make them close to normal levels was enabled.

[0102] Designing of a Time Dependent Release Portion

Example 10 Time Dependent Sustained Release Granules (ControlledRelease)

[0103] The core granules 3 described in Example 7 were subjected towater-insoluble film coating by a fluidized bed coating method. A recipeof a coating solution is shown in Table 3. An aminoalkyl methacrylatecopolymer RS (trade name: Eudragit RSPO, Röhm) was used as a coatingmaterial.

[0104] The dissolution profile in the JP 2 solution of granules obtainedby coating the core granules with 30 w/w % of the aminoalkylmethacrylate copolymer RS was evaluated by the JP 13 puddle method (testsolution 900 ml: 50 rpm). The dissolution rate of nateglinide wascontrolled in comparison with the immediate release granules. Therelease control presumed to be effective mainly for decreasing a fastingblood glucose level to make it close to a normal level was enabled.TABLE 3 aminoalkyl methacrylate copolymer 7.0% Macrogol 6000 0.7% talc3.5% ethanol 70.0%  water 18.8% 

Example 11 Dissolution Profile when Mixing Immediate Release Granuleswith Time Dependent Sustained Release Granules

[0105] The dissolution profile in the JP 2 solution when mixing theimmediate release granules described in Example 1 with the timedependent sustained release granules described in Example 10 (5:5nateglinide weight ratio) was evaluated by the JP 13 puddle method (testsolution 900 ml: 50 rpm). The drug was released at a rate of 50% within30 minutes, and the drug was then gradually released over a period 6hours. The release control presumed to be effective for decreasing apost prandial blood glucose level and a fasting blood glucose level tomake them close to normal levels was enabled.

Example 12 Time Limit Release Granules (Controlled Release)

[0106] The coating core granules 1 described in Example 5 were subjectedto water-insoluble film coating by a fluidized bed coating method. Arecipe of a coating solution is shown in Table 3 above. An aminoalkylmethacrylate copolymer RS (trade name: Eudragit RSPO, Röhm) was used asa coating material. The dissolution profile in the JP 2 solution ofgranules obtained by coating the core granules with 30.0 w/w % of theaminoalkyl methacrylate copolymer RS was evaluated by the JP 13 puddlemethod (test solution 900 ml: 50 rpm). Nateglinide was little releasedfrom the granules till 2 hours from the start-up of the dissolutiontest. However, nateglinide was then rapidly released. The releasecontrol presumed to be effective mainly for decreasing a fasting bloodglucose level to make it close to a normal value was enabled.

Example 13 Dissolution Profile when Mixing Immediate Release Granuleswith Time Limit Release Granules

[0107] The dissolution profile in the JP 2 solution when mixing theimmediate release granules described in Example 1 with the time limitrelease granules described in Example 12 (5:5 nateglinide weight ratio)was evaluated by the JP 13 puddle method (test solution 900 ml: 50 rpm).The drug was released at a rate of 50% within 30 minutes, and two hourslater, the remaining drug was rapidly released. The release controlpresumed to be effective for decreasing a post prandial blood glucoselevel and a fasting blood glucose level to make them close to normallevels was enabled.

Example 14 Evaluation of Change in Blood Glucose Level by Administrationof a Controlled Release Portion (Enteric Coated Granules)

[0108] The enteric coated granules A, B and C were administered as acontrolled release portion to Beagle dogs just before feeding (9 mg/kgas nateglinide), and the change in blood glucose level was evaluated.Consequently, it was found that in comparison with the control (feedonly), the enteric coated granules A and B decreased mainly a fastingblood glucose level and the enteric coated granules C decreased both afasting blood glucose level and a post prandial blood glucose level tomake them close to normal levels (FIG. 8).

Example 15 Evaluation of Change in Blood Glucose Level by SimultaneousAdministration of an Immediate Release Portion and a Controlled ReleasePortion (Enteric Coated Granules)

[0109] An immediate release portion (nateglinide: 60 mg) and entericcoated granules A (nateglinide: 90 mg) were administered to Beagle dogsjust before feeding, and a change in blood glucose level was evaluated.Consequently, it was found that in comparison with the control (feedonly), both a fasting blood glucose level and a post prandial bloodglucose level were decreased to make them close to normal levels (FIG.9).

Example 16 Emulsion Preparation (Controlled Release)

[0110] One gram of nateglinide, 3.0 g of soybean lecithin and 0.5 g ofpolyoxyethylene hardened castor oil 60 were dissolved in 60 ml ofdichloromethane, and dichloromethane was distilled off with anevaporator. The resulting oil was vacuum-dried at 60° C. for 3 hours ormore. The resulting oil was vigorously dispersed in 200 ml of waterusing a homogenizer, and then adjusted to pH of 7.5 with 0.5 mol/litersodium hydroxide to obtain a nateglinide emulsion preparation.

Example 17 Emulsion Preparation (Controlled Release)

[0111] One gram of nateglinide, 1.0 g of corn oil and 2.0 g ofpolysorbate 80 were uniformly mixed. The resulting oil was vigorouslydispersed in 100 ml of water using a homogenizer, and then adjusted topH of 5.9 with a 0.5 mol/liter sodium hydroxide aqueous solution toobtain a nateglinide emulsion preparation.

Example 18 Microcapsule Preparation (Controlled Release)

[0112] Five grams of nateglinide and 15 g of polylactic acid weredissolved in dichloromethane. With vigorous stirring, thisdichloromethane solution was slowly added to 1,000 ml of a 0.5 w/v %polyvinyl alcohol aqueous solution to obtain a dispersion.Dichloromethane was distilled off from the thus-obtained dispersion by aprocedure at an elevated temperature under reduced pressure.

[0113] This dispersion was put in a centrifugal separator to precipitatemicrocapsule fractions. The supernatant was removed, and microcapsuleswere redispersed with the addition of water. This washing procedure wasconducted twice.

[0114] The microcapsule dispersion after washing was freeze-dried toobtain a nateglinide microcapsule dispersion.

Example 19 Evaluation of Change in Blood Glucose Level by SimultaneousAdministration of an Immediate Release Portion and a Controlled ReleasePortion (Enteric Coated Granules) (Evaluation of Dose Dependence of aControlled Release Portion)

[0115] An immediate release portion (nateglinide: 60 mg) and entericcoated granules A (nateglinide: 60 or 90 mg) were administered to Beagledogs just before feeding, and a change in concentration of nateglinidein plasma and a change in blood glucose level were evaluated.

[0116] In the change in concentration of nateglinide in plasma, with theincrease in dose of the enteric coated granules A, Cmax (maximumconcentration in plasma) was almost unchanged, whereas a tendency of theincrease in concentration of nateglinide in plasma was observed in 4 to9 hours after the administration (FIG. 10).

[0117] In the blood glucose level, with the increase in dose of theenteric coated granules A, a tendency of controlling the blood glucoselevel in 4 to 9 hours after the administration was observed. As inExample 15, it was found that the combination of the immediate releaseportion and the controlled release portion decreased both a postprandial blood glucose level and a fasting blood glucose level to makethem close to normal levels, and the effect of the amount of thecontrolled release portion was identified as a tendency (FIG. 11).

Example 20 Erosion Matrix Tablets and Erosion Matrix Coated Tablets(Controlled Release Portion)

[0118] One hundred grams of nateglinide, 25.0 g of hydroxypropylmethylcellulose and 41.7 g of micro-crystalline cellulose were charged in ahigh-speed agitation granulator, and mixed. Then, 90.0 g of water wasadded, and granulation was conducted for 1.5 minutes. The resultinggranular product was dried on a shelf, and screened using a sieve withan opening of 850 μm. This procedure was conducted twice for mixing toobtain 317 g of the granular product.

[0119] The thus-obtained granular product was mixed with 6.47 g ofmagnesium stearate, and the mixture was tableted to obtain erosionmatrix tablets.

[0120] The resulting erosion matrix tablets were coated using a coatingsolution formed by dissolving 50.0 g of hydroxypropylmethyl celluloseand 10.0 g of macrogol 6000 in 1,440 g of water (12.5% ofhydroxypropylmethyl cellulose based on the weight of the erosion matrixtablet was coated) to obtain erosion matrix coated tablets.

Example 21 Dissolution Profile of Erosion Matrix Tablets and ErosionMatrix Coated Tablets

[0121] The dissolution profiles in the JP 2 solution of the erosionmatrix tablets and the erosion matrix coated tablets obtained in Example20 were evaluated by the JP 13 puddle method (test solution 900 ml: 50rpm). The erosion matrix tablets controlled the dissolution rate ofnateglinide in comparison with the immediate release granules (FIG. 12).In the erosion matrix coated tablets, a lag time of 50 minutes wasobserved in the dissolution in comparison with the erosion matrixtablets (FIG. 12).

[0122] The controlled release considered mainly effective for decreasinga fasting blood glucose level to make it close to a normal value wasenabled.

Example 22 Dry Coated Tablets Using Erosion Matrix Tablets as an InnerShell

[0123] Dry coated tablets were produced using the erosion matrix tabletsobtained in Example 21 and the immediate release granules obtained inExample 1 (erosion matrix tablets: 153 mg, immediate release granules:236.4 mg, magnesium stearate: 3.6 g, tablet diameter: 10 mm φ).

Example 23 Dissolution Profile of Dry Coated Tablets

[0124] The dissolution profile in the JP 2 solution of the dry coatedtablets described in Example 22 was evaluated by the JP 13 puddle method(test solution 900 ml: 50 rpm). The drug was dissolved at a rate of 44%within 30 minutes, and then gradually released. In 3 hours, the ratereached 62% (FIG. 13). The release control presumed to be effective fordecreasing a post prandial blood glucose level and a fasting bloodglucose level to make them close to normal levels was enabled.

Example 24 Change in Concentration of Nateglinide of Dry Coated Tabletsin Plasma and Change in Blood Glucose Level on Dogs

[0125] The dry coated tablets obtained in Example 22 were administeredto Beagle dogs just before feeding, and the change in concentration ofnateglinide in plasma and the change in blood glucose level wereevaluated.

[0126] In the change in concentration of nateglinide in plasma, it wasfound that in comparison with the immediate release preparation, Cmaxwas not increased so high but the concentration of nateglinide in plasmawas maintained high for 9 hours after the administration (FIG. 14).

[0127] With respect to the blood glucose level, it was found that both apost prandial blood glucose level and a fasting blood glucose level weredecreased (FIG. 15).

[0128] According to the invention, both a post prandial blood glucoselevel and a fasting blood glucose level could directly be decreased withone preparation to make them close to normal levels.

[0129] Further, in the invention, one preparation provides the followingadvantages. (1) Even though other preparations are taken, a possibilityof erroneous administration is decreased. (2) it is handy to carry. (3)There is a case where one preparation is administered before eating andanother preparation after eating, and in this case, in an erroneousadministration timing, no effect might be provided or a serious sideeffect (hypoglycemic condition) might occur. However, one preparationcan avoid this possibility. (4) The costs that patients bear aredecreased.

1. A controlled release oral anti-diabetic preparation comprising atleast one fast-acting post prandial blood glucose regulator.
 2. Thepreparation of claim 1, further comprising said fast-acting postprandial blood glucose regulator in an immediate release form and acontrolled release form.
 3. The preparation of claim 1, wherein thefast-acting post prandial blood glucose regulator is nateglinide ormitiglinide.
 4. The preparation of claim 2, wherein the fast-acting postprandial blood glucose regulator is nateglinide or mitiglinide.
 5. Thepreparation of claim 1, wherein the fast-acting post prandial bloodglucose regulator is nateglinide or mitiglinide dispersed in a matrixand/or coated with a material selected from the group consisting ofpolysaccharide derivatives, polyacrylic acid derivatives,polyoxyethylene derivatives and polyvinyl pyrrolidone derivatives tocontrol the release of said nateglinide or mitiglinide.
 6. Thepreparation of claim 1, wherein the fast-acting post prandial bloodglucose regulator is nateglinide or mitiglinide dispersed in a matrixand/or coated with a material selected from the group consisting ofcellulose derivatives, an ethyl acrylate•methylmethacrylate•chlorotrimethylammoniumethyl methacrylate copolymer, amethacrylic acid•methyl methacrylate copolymer, a methacrylic acid•ethylacrylate copolymer, polyoxyethylene and polyvinyl pyrrolidone.
 7. Thepreparation of claim 1, wherein the fast-acting post prandial bloodglucose regulator is nateglinide or mitiglinide dispersed in a matrixcomprising hydroxypropylmethyl cellulose.
 8. The preparation claim 1,wherein the fast-acting post prandial blood glucose regulator isnateglinide or mitiglinide dispersed in a matrix comprisinghydroxypropylmethyl cellulose and having a coating comprisinghydroxypropylmethyl cellulose.
 9. The preparation of claim 1, whichcomprises a multi-layer tablet wherein said fast-acting post prandialblood glucose regulating agent is nateglinide or mitiglinide, whereinsaid tablet comprises a controlled release layer comprising nateglinideor mitiglinide dispersed in a matrix comprising a material selected fromthe group consisting of polysaccharide derivatives, polyacrylic acidderivatives, polyoxyethylene derivatives and polyvinyl pyrrolidonederivatives and an immediate release layer comprising nateglinide ormitiglinide.
 10. The preparation of claim 1, which comprises a tabletwherein the fast-acting post prandial blood glucose regulator isnateglinide or mitiglinide, wherein said tablet comprises a controlledrelease inner layer comprising natiglinide disperse in ahydroxypropylmethyl cellulose matrix and an immediate release layercomprising nateglinide or mitiglinide.
 11. The preparation of claim 1,which comprises a tablet wherein the fast-acting post prandial bloodglucose regulator is nateglinide or mitiglinide, wherein said tablecomprises a controlled release inner shell comprising nateglinide ormitiglinide dispersed in a matrix comprising a material selected fromthe group consisting of polysaccharide derivatives, polyacrylic acidderivatives, polyoxyethylene derivatives and polyvinyl pyrrolidonederivatives and an immediate release outer shell comprising nateglinideor mitiglinide.
 12. The preparation of claim 1, which comprises a tabletwherein the fast-acting post prandial blood glucose regulator isnateglinide or mitiglinide, wherein said tablet comprises a controlledrelease inner shell comprising nateglinide or mitiglinide dispersed in amatrix comprising hydroxypropylmethyl cellulose and an immediate releaseouter shell comprising nateglinide or mitiglinide.
 13. The preparationof claim 1, wherein the fast-acting post prandial blood glucoseregulator is nateglinide or mitiglinide coated with at least oneentereic material selected from the group consisting of a methacrylicacid methyl methacrylate copolymer, a methacrylic acid ethyl acrylatecopolymer, and hydroxypropylmethyl cellulose phthalate.
 14. Thepreparation of claim 1, wherein the fast-acting post prandial bloodglucose regulator is nateglinide or mitiglinide, wherein said controlledrelease form comprises nateglinide or mitiglinide coated with at leastone enteric material selected from the group consisting of a methacrylicacid copolymer LD, a dry methacrylic acid copolymer LD, a methacrylicacid methylmethacrylate copolymer, a methacrylic acid copolymer S,hydroxypropylmethyl cellulose phthalate, and said immeidate release formcomprises nateglinide or mitiglinide.
 15. The preparation of claim 2,wherein the fast-acting post prandial blood glucose regulator isnateglinide or mitiglinide dispersed in a matrix and/or coated with amaterial selected from the group consisting of polysaccharidederivatives, polyacrylic acid derivatives, polyoxyethylene derivativesand polyvinyl pyrrolidone derivatives to control the release of saidnateglinide or mitiglinide.
 16. The preparation of claim 2, wherein thefast-acting post prandial blood glucose regulator is nateglinide ormitiglinide dispersed in a matrix and/or coated with a material selectedfrom the group consisting of cellulose derivatives, an ethyl acrylatemethyl methacrylate chlorotrimethylammoniumethyl methacrylate copolymer,a methacrylic acid methyl methacrylate copolymer, a methacrylic acidethyl acrylate copolymer, polyoxyethylene and polyvinyl pyrrolidone. 17.The preparation of claim 2, wherein the fast-acting post prandial bloodglucose regulator is nateglinide or mitiglinide dispersed in a matrixcomprising hydroxypropylmethyl cellulose.
 18. The preparation claim 2,wherein the fast-acting post-prandial blood glucose regulator isnateglinide or mitiglinide dispersed in a matrix comprisinghydroxypropylmethyl cellulose and having a coating comprisinghydroxypropylmethyl cellulose.
 19. The preparation of claim 2, whichcomprises a multi-layer tablet wherein said fast-acting post prandialblood glucose regulating agent is nateglinide or mitiglinide, whereinsaid tablet comprises a controlled release layer comprising nateglinideor mitiglinide dispersed in a matrix comprising a material selected fromthe group consisting of polysaccharide derivatives, polyacrylic acidderivatives, polyoxyethylene derivatives and polyvinyl pyrrolidonederivatives and an immediate release layer comprising nateglinide ormitiglinide.
 20. The preparation of claim 2, which comprises amulti-layer table wherein said fast-acting post prandial blood glucoseregulating agent is nateglinide or mitiglinide, wherein said tabletcomprises a controlled release layer comprising nateglinide ormitiglinide dispersed in a hydroxypropylmethyl cellulose matrix and animmediate release layer comprising nateglinide or mitiglinide.
 21. Thepreparation of claim 2, which comprises a tablet wherein the fast-actingpost prandial blood glucose regulator is nateglinide or mitiglinide,wherein said table comprises a controlled release inner shell comprisingnateglinide or mitiglinide dispersed in a matrix comprising a materialselected from the group consisting of polysaccharide derivatives,polyacrylic acid derivatives, polyoxyethylene derivatives and polyvinylpyrrolidone derivatives and an immediate release outer shell comprisingnateglinide or mitiglinide.
 22. The preparation of claim 2, whichcomprises a tablet wherein the fast-acting post prandial blood glucoseregulator is nateglinide or mitiglinide, wherein said tablet comprises acontrolled release inner shell comprising nateglinide or mitiglinidedispersed in a matrix comprising hydroxypropylmethyl cellulose and animmediate release outer shell comprising nateglinide or mitiglinide. 23.The preparation of claim 2, wherein the fast-acting post prandial bloodglucose regulator is nateglinide or mitiglinide coated with at least oneenteric material selected from the group consisting of a methacrylicacid methyl methacrylate copolymer, a methacrylic acid ethyl acrylatecopolymer, and hydroxypropylmethyl cellulose phthalate.
 24. Thepreparation of claim 1, wherein the fast-acting post prandial bloodglucose regulator is nateglinide or mitiglinide, wherein said controlledrelease form comprises nateglinide or mitiglinide coated with at leastone enteric material selected from the group consisting of a methacrylicacid copolymer LD, a dry methacrylic acid copolymer LD, a methacrylicacid methylmethacrylate copolymer, a methacrylic acid copolymer S,hydroxypropylmethyl cellulose phthalate, and said immediate release formcomprises nateglinide or mitiglinide.
 25. The preparation of claim 1,which further comprises at least one member selected from the groupconsisting of α-glycosidase inhibitors, sulfanylurea drugs, biguanidedrugs, and insulin sensitizers.
 26. The preparation of claim 25, whichcontains a α-glycosidase inhibitor.
 27. The preparation of claim 26,wherein the α-glycosidase inhibitor is acarbose.
 28. The preparation ofclaim 25, which contains a sulfonylurea drug.
 29. The preparation ofclaim 28, wherein the sulfonylurea drug is tolbutamide.
 30. Thepreparation of claim 25, which contains a biguanide drug.
 31. Thepreparation of claim 30, wherein the biguanide drug is metformin. 32.The preparation of claim 25, which contains an insulin sensitizer. 33.The preparation of claim 32, wherein the insulin sensitizer istroglitazone.
 34. An anti-diabetic preparation for oral administrationcomprising an fast-acting post prandial blood glucose regulator having acoating comprising hydroxypropylmethyl cellulose phthalate sufficient toprovide continuous release of said drug as the sole active ingredientfor decreasing blood glucose levels.
 35. The preparation of claim 34,wherein the fast-acting post prandial blood glucose regulator isnateglinide or mitiglinide.
 36. A method of controlling both postprandial blood glucose levels and fasting blood glucose levels by orallyadministering to a patient an effective amount of a controlled releasecomposition comprising at least one fast-acting post prandial bloodglucose regulator.
 37. The method of claim 36, wherein said at least onefast-acting post prandial blood glucose regulator is the sole regulatorof blood glucose levels in said controlled release composition.
 38. Themethod of claim 36, wherein said at least one fast-acting post prandialblood glucose regulator is nateglinide or mitiglinide.
 39. The method ofclaim 36, wherein said controlled release composition also comprises atleast one fast-acting post prandial blood glucose regulator in immediaterelease form.
 40. The method of claim 39, wherein said controlledrelease composition comprises the same fast-acting post prandial bloodglucose regulator as the controlled release and immediate release formsof the fast-acting post prandial blood glucose regulator.
 41. The methodof claim 40, wherein said fast-acting post prandial blood glucoseregulator is nateglinide or mitiglinide.
 42. The method of claim 36,wherein the controlled release composition also comprises a biguanidedrug.
 43. The method of claim 42, wherein said biguanide drug ismetformin.
 44. A method of controlling both post prandial blood glucoselevels and fasting blood glucose levels, comprising orally administeringto a patient an effective amount of a the preparation of claim
 1. 45. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 2. 46. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 3. 47. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 4. 48. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 5. 49. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 6. 50. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 7. 51. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 8. 52. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 9. 53. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 10. 54. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 11. 55. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 12. 56. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 13. 57. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 14. 58. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 15. 59. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 16. 60. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 17. 61. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 18. 62. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 19. 63. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 20. 64. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 21. 65. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 22. 66. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of a the preparation of claim
 23. 67. Amethod of controlling both post prandial blood glucose levels andfasting blood glucose levels, comprising orally administering to apatient an effective amount of the preparation of claim
 24. 68. A methodof controlling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 25. 69. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 26. 70. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 27. 71. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 28. 72. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 29. 73. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of thc preparation of claim
 30. 74. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 31. 75. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 32. 76. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 33. 77. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 34. 78. A method ofcontrolling both post prandial blood glucose levels and fasting bloodglucose levels, comprising orally administering to a patient aneffective amount of the preparation of claim
 35. 79. A method oftreating diabetes, comprising orally administering to a patient aneffective amount of the preparation of claim
 1. 80. A method of treatingdiabetes, comprising orally administering to a patient an effectiveamount of the preparation of claim
 2. 81. A method of treating diabetes,comprising orally administering to a patient an effective amount of thepreparation of claim
 3. 82. A method of treating diabetes, comprisingorally administering to a patient an effective amount of the preparationof claim
 4. 83. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 5. 84. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 6. 85. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 7. 86. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 8. 87. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 9. 88. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 10. 89. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 11. 90. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 12. 91. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 13. 92. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 14. 93. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 15. 94. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 16. 95. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 17. 96. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 18. 97. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 19. 98. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 20. 99. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 21. 100. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 22. 101. A method of treating diabetes, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 23. 102. The preparation of claim 1, the fast-acting post prandialblood glucose regulator is nateglinide.
 103. The preparation of claim 1,wherein the fast-acting post prandial blood glucose regulator ismitiglinide.
 104. The preparation of claim 34, the fast-acting postprandial blood glucose regulator is nateglinide.
 105. The preparation ofclaim 34, wherein the fast-acting post prandial blood glucose regulatoris mitiglinide.
 106. The method of claim 36, the fast-acting postprandial blood glucose regulator is nateglinide.
 107. The method ofclaim 36, wherein the fast-acting post prandial blood glucose regulatoris mitiglinide.
 108. A method of controlling both post prandial bloodglucose levels and fasting blood glucose levels, comprising orallyadministering to a patient an effective amount of the preparation ofclaim
 103. 109. A method of controlling both post prandial blood glucoselevels and fasting blood glucose levels, comprising orally administeringto a patient an effective amount of the preparation of claim
 104. 110. Amethod of treating diabetes, comprising orally administering to apatient an effective amount of the preparation of claim
 103. 111. Amethod of treating diabetes, comprising orally administering to apatient an effective amount of the preparation of claim 104.